Skip to main content

Advertisement

SpringerLink
Log in

Dipeptidyl peptidase-4 inhibitors do not increase the risk of cardiovascular events in type 2 diabetes: a cohort study

  • Original Article
  • Published:
Acta Diabetologica Aims and scope Submit manuscript

Abstract

Aims

Two recent randomized controlled trials of type 2 diabetes mellitus (T2DM) patients with history of, or at high risk of, cardiovascular disease (CVD) showed no risk of ischemic cardiovascular events associated with dipeptidyl peptidase-4 inhibitors (DPP4i), but an increased risk of heart failure (HF) with saxagliptin. We evaluated the risk of CVD including myocardial infarction (MI), stroke, coronary revascularization, and HF associated with DPP4i in T2DM patients with and without baseline CVD as used in the community.

Methods

Using US commercial insurance claims data (2005–2012), we conducted a cohort study that included initiators of DPP4i and non-DPP4i treatments. Composite CVD endpoints including MI, stroke, coronary revascularization, and HF were defined with a hospital discharge diagnosis or procedure code. Cox proportional hazards models compared the risk of composite and individual CVD endpoints in propensity score (PS)-matched initiators of DPP4 versus non-DPP4i.

Results

We included 79,538 (18 % with baseline CVD) persons in PS-matched pairs of DPP4i and non-DPP4i initiators. The incidence rate per 1,000 person-years for composite CVD was 30.30 (95 % CI 28.24–32.51) in DPP4i and 34.76 (95 % CI 32.34–37.36) in non-DPP4i. The PS-matched hazard ratio (HR) for composite CVD was 0.87 (95 % CI 0.79–0.96) in DPP4i versus non-DPP4i. The PS-matched HR for HF was 0.81 (95 % CI 0.70–0.94) in DPP4i versus non-DPP4i. Among patients with baseline CVD, there was no increased risk of CVD or HF associated with DPP4i use.

Conclusions

Among T2DM patients, initiating DPP4i was not associated with a greater risk of CVD or HF compared to non-DPP4i initiators.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

CVD:

Cardiovascular disease

DM:

Diabetes mellitus

DPP4i:

Dipeptidyl peptidase-4 inhibitors

HbA1c:

Glycated hemoglobin

HF:

Heart failure

HR:

Hazard ratio

ICD-9 CM:

International Classification of Diseases, Ninth Revision, Clinical Modification 9th edition

PS:

Propensity score

RCT:

Randomized controlled trial

T2DM:

Type 2 diabetes

TZD:

Thiazolidinedione

References

  1. Amori RE, Lau J, Pittas AG (2007) Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis. JAMA 298(2):194–206

    Article  CAS  PubMed  Google Scholar 

  2. Karagiannis T, Paschos P, Paletas K, Matthews DR, Tsapas A (2012) Dipeptidyl peptidase-4 inhibitors for treatment of type 2 diabetes mellitus in the clinical setting: systematic review and meta-analysis. BMJ 344:e1369

    Article  PubMed  Google Scholar 

  3. Aschner P, Kipnes MS, Lunceford JK, Sanchez M, Mickel C, Williams-Herman DE (2006) Sitagliptin Study 021 Group: effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care 29(12):2632–2637

    Article  CAS  PubMed  Google Scholar 

  4. Gallwitz B, Rosenstock J, Rauch T, Bhattacharya S, Patel S, von Eynatten M, Dugi KA, Woerle HJ (2012) 2-year efficacy and safety of linagliptin compared with glimepiride in patients with type 2 diabetes inadequately controlled on metformin: a randomised, double-blind, non-inferiority trial. Lancet 380(9840):475–483

    Article  CAS  PubMed  Google Scholar 

  5. DeFronzo RA, Fleck PR, Wilson CA, Mekki Q (2008) Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes and inadequate glycemic control: a randomized, double-blind, placebo-controlled study. Diabetes Care 31(12):2315–2317

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Faillie JL, Azoulay L, Patenaude V, Hillaire-Buys D, Suissa S (2014) Incretin based drugs and risk of acute pancreatitis in patients with type 2 diabetes: cohort study. BMJ 348:g2780

    Article  PubMed Central  PubMed  Google Scholar 

  7. Li L, Shen J, Bala MM, Busse JW, Ebrahim S, Vandvik PO, Rios LP, Malaga G, Wong E, Sohani Z et al (2014) Incretin treatment and risk of pancreatitis in patients with type 2 diabetes mellitus: systematic review and meta-analysis of randomised and non-randomised studies. BMJ 348:g2366

    Article  PubMed Central  PubMed  Google Scholar 

  8. Grundy SM, Benjamin IJ, Burke GL, Chait A, Eckel RH, Howard BV, Mitch W, Smith SC Jr, Sowers JR (1999) Diabetes and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation 100(10):1134–1146

    Article  CAS  PubMed  Google Scholar 

  9. Wit MA, de Mulder M, Jansen EK, Umans VA (2013) Diabetes mellitus and its impact on long-term outcomes after coronary artery bypass graft surgery. Acta Diabetol 50(2):123–128

    Article  CAS  PubMed  Google Scholar 

  10. Tarquini R, Lazzeri C, Pala L, Rotella CM, Gensini GF (2011) The diabetic cardiomyopathy. Acta Diabetol 48(3):173–181

    Article  PubMed  Google Scholar 

  11. Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, Ohman P, Frederich R, Wiviott SD, Hoffman EB et al (2013) Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 369(14):1317–1326

    Article  CAS  PubMed  Google Scholar 

  12. White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, Perez AT, Fleck PR, Mehta CR, Kupfer S et al (2013) Alogliptin after Acute Coronary Syndrome in Patients with Type 2 Diabetes. N Engl J Med 369(14):1327–1335

    Article  CAS  PubMed  Google Scholar 

  13. White WB (2013) Results from examine. In: 49th European Association for the Study of Diabetes September 26 2013, Barcelona, Spain

  14. American Diabetes Association (2014) Standards of medical care in diabetes–2014. Diabetes Care 37(Suppl 1):S14–80

  15. Lipscombe LL, Gomes T, Levesque LE, Hux JE, Juurlink DN, Alter DA (2007) Thiazolidinediones and cardiovascular outcomes in older patients with diabetes. JAMA 298(22):2634–2643

    Article  CAS  PubMed  Google Scholar 

  16. Andrade SE, Harrold LR, Tjia J, Cutrona SL, Saczynski JS, Dodd KS, Goldberg RJ, Gurwitz JH (2012) A systematic review of validated methods for identifying cerebrovascular accident or transient ischemic attack using administrative data. Pharmacoepidemiol Drug Saf 21(Suppl 1):100–128

    Article  PubMed Central  PubMed  Google Scholar 

  17. Saczynski JS, Andrade SE, Harrold LR, Tjia J, Cutrona SL, Dodd KS, Goldberg RJ, Gurwitz JH (2012) A systematic review of validated methods for identifying heart failure using administrative data. Pharmacoepidemiol Drug Saf 21(Suppl 1):129–140

    Article  PubMed  Google Scholar 

  18. Kiyota Y, Schneeweiss S, Glynn RJ, Cannuscio CC, Avorn J, Solomon DH (2004) Accuracy of medicare claims-based diagnosis of acute myocardial infarction: estimating positive predictive value on the basis of review of hospital records. Am Heart J 148(1):99–104

    Article  PubMed  Google Scholar 

  19. Choma NN, Griffin MR, Huang RL, Mitchel EF Jr, Kaltenbach LA, Gideon P, Stratton SM, Roumie CL (2009) An algorithm to identify incident myocardial infarction using Medicaid data. Pharmacoepidemiol Drug Saf 18(11):1064–1071

    Article  PubMed  Google Scholar 

  20. Gagne JJ, Glynn RJ, Avorn J, Levin R, Schneeweiss S (2011) A combined comorbidity score predicted mortality in elderly patients better than existing scores. J Clin Epidemiol 64(7):749–759

    Article  PubMed Central  PubMed  Google Scholar 

  21. Rubin D (1997) Estimating causal effects from large data sets using propensity scores. Ann Intern Med 127(8 Pt 2):757–763

    Article  CAS  PubMed  Google Scholar 

  22. Austin PC (2007) The performance of different propensity score methods for estimating marginal odds ratios. Stat Med 26(16):3078–3094

    Article  PubMed  Google Scholar 

  23. Austin PC (2009) Some methods of propensity-score matching had superior performance to others: results of an empirical investigation and Monte Carlo simulations. Biom J Biom Z 51(1):171–184

    Article  Google Scholar 

  24. Kleinbaum D, Klein M (2012) Evaluating the proportional hazards assumption. In: Gail M, Krickberg K, Samet J, Tsiatis A, Wong W (eds) Survival analysis: A self-learning text, 3rd edn. Springer, Berlin

    Chapter  Google Scholar 

  25. White WB, Pratley R, Fleck P, Munsaka M, Hisada M, Wilson C, Menon V (2013) Cardiovascular safety of the dipetidyl peptidase-4 inhibitor alogliptin in type 2 diabetes mellitus. Diabetes Obes Metab 15(7):668–673

    Article  CAS  PubMed  Google Scholar 

  26. McMurray J (2013) The Vildagliptin in Ventricular Dysfunction Diabetes trial (VIVIDD). In: European Society of Cardiology Heart Failure Association: May 26 2013, Lisbon, Portugal: 99

  27. Ussher JR, Drucker DJ (2012) Cardiovascular biology of the incretin system. Endocr Rev 33(2):187–215

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Johnson ES, Bartman BA, Briesacher BA, Fleming NS, Gerhard T, Kornegay CJ, Nourjah P, Sauer B, Schumock GT, Sedrakyan A et al (2013) The incident user design in comparative effectiveness research. Pharmacoepidemiol Drug Saf 22(1):1–6

    Article  PubMed  Google Scholar 

  29. Ray WA (2003) Evaluating medication effects outside of clinical trials: new-user designs. Am J Epidemiol 158(9):915–920

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

Kim was supported by the NIH grant K23 AR059677. Goldfine is supported by the NIH grants R56 DK095451, P50 HL083813, R01 DK088214, U01 HL101422, P30-DK03836, and American Diabetes Association 7-13-CE-17.

Conflict of interest

Kim received research support from Pfizer, Inc, Glynn received research grants from AstraZeneca and Novartis, Liu has no conflict of interest, Everett receives research support from Roche Diagnostics and Novartis and Goldfine receives research support in the form of materials and supplies from Amneal Pharmaceuticals; Lifescan, a Division of Johnson and Johnson; Novo Nordisk; Mercodia and Nestle, Inc.

Human and Animal Rights disclosure

The study protocol was approved by the Institutional Review Board of the Brigham and Women’s Hospital. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008.

Informed consent disclosure

Patient informed consent was not required as the dataset was de-identified to protect subject confidentiality.

Author information

Authors and Affiliations

  1. Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA, USA

    Seoyoung C. Kim, Robert J. Glynn & Jun Liu

  2. Division of Rheumatology, Allergy and Immunology, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA, USA

    Seoyoung C. Kim

  3. Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, MA, USA

    Brendan M. Everett

  4. Clinical Research, Joslin Diabetes Center, 1 Joslin Pl, Boston, MA, USA

    Allison B. Goldfine

  5. 1620 Tremont Street, Suite 3030, Boston, MA, 02120, USA

    Seoyoung C. Kim

Authors
  1. Seoyoung C. Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert J. Glynn
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jun Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Brendan M. Everett
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Allison B. Goldfine
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Seoyoung C. Kim.

Additional information

Managed by Antonio Secchi.

Prior Presentation Parts of this study were presented in abstract form at the ICE/ENDO 2014 meeting in Chicago, IL, 21–24 June 2014.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kim, S.C., Glynn, R.J., Liu, J. et al. Dipeptidyl peptidase-4 inhibitors do not increase the risk of cardiovascular events in type 2 diabetes: a cohort study. Acta Diabetol 51, 1015–1023 (2014). https://doi.org/10.1007/s00592-014-0663-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00592-014-0663-2

Keywords

Search

Navigation